General Introduction to Sensory Mechanisms Peter McNaughton DBSF Università di Insubria, Department of Pharmacology Varese Tennis Court Road, Cambridge 11 April 2006 CB2 1QJ Descartes’ theory of sensory signalling An early view of sensory transduction, by René Descartes (1644). In describing this remarkably prescient hypothesis Descartes says: “If for example the fire (A) comes near the foot (B), the minute particles of this fire, which as you know move with great velocity, have the power to set in motion the spot of the skin of the foot which they touch, and by this means pulling on the delicate thread (cc) they open up at the same instant the pore (d e) against which the delicate thread ends, just as by pulling against one end of a rope one makes to strike at the same instant a bell which hangs at the other end” The role of chance in science We shall compare two very different sensory systems: - Vision - Somatic sensation Receptors are specialised to detect particular sensory modalities and stimulus intensities Vision: rods and cones •Rods react slowly but with high sensitivity •Cones respond more rapidly Cones detect different wavelengths In the somatosensory system different receptors detect different stimulus modalities Frequency responses of two rapidly adapting mechanoreceptors Receptors for warmth and cold Receptive field size depends on receptor type as well as on the extent of spread of terminals How different receptors respond to real stimuli (Braille dots) Receptors transduce energy of their preferred modality into an electrical signal The first step is that the energy of the incoming stimulus must be detected Retinal absorbs single photons of light The conformational change in retinal drives a conformational change at the cytoplasmic face of rhodopsin Amplification steps follow Photoreceptors amplify the signal in a G- protein coupled amplification cascade One absorbed photon obstructs the passage of c. 1,000,000 Na+ ions in a dark-adapted rod Closure of outer segment ion channels leads to hyperpolarisation In somatosensory receptors the detector is often simply an ion channel Example: ion channels activated by painful stimuli All sensory receptors adapt Illumination causes the gain to be reduced at each major step in photoreceptors Somatosensory receptors can be divided into rapidly and slowly adapting types Rapid adaptation depends on accessory structures Particular features of pain sensation Nobody likes pain……… …but pain is essential for survival. Twelve year old boy with complete lack of sensitivity to pain. Note missing digits (result of autophagy) and ulcer on knee. People with chronic pain insensitivity usually die young from accidents, internal bleeding, burns etc. Chronic pain insensitivity is due to a genetic defect in the TrkA receptor which binds NGF. Pain-sensitive nerve fibres consequently fail to innervate their targets. Pain is in some ways different from other sensations We can fail to notice pain which in normal circumstances would be unbearable …. “This comes to tell you that I am alive and hearty except three fingers; but that's not much, it might have been my head. How my fingers got knocked overboard I don't know, but off they are, and I never missed them till I wanted them.” Sailor from Collingwood's ship the Royal Sovereign writing to his father after the battle of Trafalgar …..but pain can be felt in the absence of any stimulus “Verily it is a thing wonderous strange and prodigious, and which will scarce be credited, unless by such as have seen with their eyes, the patients who have many months after the cutting away of the leg, greviously complained that they yet feel exceeding great pain of that leg so cut off.” Ambroise Pare, physician, 1552 Pain receptors Are there specific pain receptors, or nociceptors, as postulated by Sherrington in 1905, or does pain result from overstimulation of normal touch etc. receptors? In the 1960s Ed Perl recorded action potentials from single afferent nerve fibres. He found separate classes of nerve terminals responding only to high-threshold stimuli. Some were myelinated Ad fibres, but many were unmyelinated C fibres. So nociceptors do exist, as Sherrington originally proposed. Typically they respond to a range of noxious stimuli – i.e. they are polymodal. How do nociceptors respond to a painful stimulus? Generator current and action potentials: noxious heat stimulus What factors can excite and sensitize nociceptors? Ion channels involved in nociceptor excitation TRPV1 is an ion channel gated by heat, capsaicin and acid proton sensors E648 E600 1 2 3 4 5 6 capsaicin binding site S502 S800 PKCe S116 COOH NH2 PKA Sensitization process at the peripheral terminal: prostaglandins How does PGE2 work? Prostaglandins act via the cAMP/PKA pathway Sensitization process at the peripheral terminal: bradykinin Bradykinin sensitizes the heat response by increasing current through TRPV1 How does bradykinin work? Bradykinin acts via the PKC pathway A possible future analgesic: Cannabis May have promise in e.g. multiple sclerosis, neuropathic pain Acupuncture gives relief from some types of pain Are we any closer to understanding pain?
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